Mesoporous silica nanoparticles accommodating electrospun nanofibers as implantable local drug delivery system processed by cold atmospheric plasma and spin coating approaches.

Nanofibers (NF) and nanoparticles are attractive for drug delivery to improve the drug bioavailability and administration. Easy manipulation of NF as macroscopic bulk material give rise to potential usages as implantable local drug delivery systems (LLDS) to overcome the failures of systemic drug delivery systems such as unmet personalized needs, side effects, suboptimal dosage. In this study, poly(ethylene glycol) polyethyleneimine (mPEG:PEI) copolymer blended polyϵ-caprolactone NFs, NFblendaccommodating mesoporous silica nanoparticles (MSN) as the implantable LLDS was achieved by employing spin coating and cold atmospheric plasma (CAP) as the post-process for accommodation on NFblend. The macroporous morphology, mechanical properties, wettability, andin vitrocytocompatibility of NFblendensured their potential as an implantable LLDS and superior features compared to neat NF. The electron microscopy images affirmed of NFblendrandom fiber (average diameter 832 ± 321 nm) alignments and accessible macropores before and after MSN@Cur accommodation. The blending of polymers improved the elongation of NF and the tensile strength which is attributed as beneficial for implantable LLDS. CAP treatment could significantly improve the wettability of NF observed by the contact angle changes from ∼126° to ∼50° which is critical for the accommodation of curcumin-loaded MSN (MSN@Cur) andin vitrocytocompatibility of NF. The combined CAP and spin coating as the post-processes was employed for accommodating MSN@Cur on NFblendwithout interfering with the electrospinning process. The post-processing aided fine-tuning of curcumin dosing (∼3 µg to ∼15 µg) per dose unit and sustained zero-order drug release profile could be achieved. Introducing of MSN@Cur to cells via LLDS promoted the cell proliferation compared to MSN@Cur suspension treatments and assigned as the elimination of adverse effects by nanocarriers by the dosage form integration. All in all, NFblend-MSN@Cur was shown to have high potential to be employed as an implantable LLDS. To the best of our knowledge, this is the first study in which mPEG:PEI copolymer blend NF are united with CAP and spin coating for accommodating nano-drug carriers, which allows for NF both tissue engineering and drug delivery applications.

Diagnostic Importance of PAX2, ARID1A, and FOXA1 Biomarkers in Atypical Endometrial Hyperplasia.

OBJECTIVE: To evaluate the contribution of PAX2, ARID1A, and FOXA1 biomarkers to diagnosis in cases with atypical endometrial hyperplasia (AEH). STUDY DESIGN: Descriptive Study. Place and Duration of the Study: Pathology Department of Umraniye Training and Research Hospital, from January 2018 to December 2020. METHODOLOGY: Curettage materials of 100 patients diagnosed with AEH which stained PAX2, ARID1A, and FOXA1, were evaluated. The staining patterns in the atypical endometrial glandular areas were grouped as slight-no loss, moderate loss, and complete loss / severe loss for all three biomarkers. Complete or/severe loss in AEH was considered helpful in the diagnosis. RESULTS: Complete loss / severe loss rates in curettages were 84% for PAX2, 5% for ARID1A, and 15% for FOXA1, respectively. When used in combination, complete loss / severe loss rates were 85% in at least one of the three markers, 84% in PAX2 and/or ARID1A, 85% in PAX2 and/or FOXA1, and 17% in ARID1A and/or FOXA1. CONCLUSION: Although all 3 biomarkers showed marked staining loss, PAX2 is the most sensitive biomarker for the diagnosis of AEH in curettage materials. KEY WORDS: Endometrium, Atypical hyperplasia, PAX2, ARID1A, FOXA1.

Opportunities for pedagogical change in Turkish medical education revealed in the wake of the COVID-19 pandemic.

Phenomenon: As the first stage of a large-scale educational design research (EDR) study focused on the complex problem of providing authentic experiential "hands-on, minds-in" learning opportunities online during a pandemic or other exigency, we conducted a literature review and we interviewed Turkish academic staff and students about their experiences during the first year of the COVID-19 Pandemic. ApproachWe interviewed faculty members, faculty members of medical education departments, and medical students from both public and private medical schools in Türkiye between October 1 and December 31, 2020. Working in pairs, we analyzed the transcripts of 49 interviews using open qualitative coding methods with satisfactory levels of coefficients of agreement. FindingsWe defined six major themes from the qualitative analysis: 1) Fear and concern were the most common reactions when first encountering the pandemic; 2) Teaching methods during the pandemic were primarily unidirectional from faculty to students. This largely one way transmission of information occurred both synchronously and asynchronously; 3) Technological support during the pandemic shutdowns was found to be challenging for both faculties and students; 4) Evaluation of learning during the pandemic was opportunistic and had questionable rigor; 5) Healthy communication was valued by both faculty and students using an array of different tools including social media; and 6) The pandemic had both negative and positive impacts on the educational processes experienced by students and provided by faculty and resulted in recommendations for new approaches to teaching and learning in the future. Medical students were primarily concerned about the susceptibility to COVID-19 of themselves and others, and how the pandemic would affect their progress toward completing their studies. Faculty were primarily concerned about the capacity of online learning to provide clinical learning opportunities and the difficulties of assessing student clinical skills using online modalities. Medical education specialists were primarily concerned about the quality of educational opportunities offered online. InsightsOur findings were similar to other studies conducted in the USA, China, United Kingdom, and other countries. However, the interviews revealed interest among faculty and medical education specialists for further investigation of experiential or active learning models that could be applied in medical education regardless of whether the delivery mode is face-to-face, online, or most likely, blended. In the next stage of our larger scale EDR study, we will design and construct prototype learning environments that incorporate experiential, active, and authentic learning design principles.

Diagnosis of COVID-19 in Patients with Acute Pulmonary Embolism.

Acute pulmonary embolism (PE) and coronavirus disease -2019 (COVID-19) are life-threatening diseases associated with significant morbidity and mortality. Yet little is known about their co-existence.This study explored clinical and laboratory differences between PE patients who tested positive with real-time reverse-transcription polymerase chain reaction (PCR+) and those who tested negative (PCR-) for SARS-CoV-2. Also, to determine whether ferritin D-dimer ratio (FDR) and platelet D-dimer ratio (PDR) can be used to predict COVID-19 in patients with PE. Files of 556 patients who underwent a computed tomography pulmonary angography (CTPA) examination were retrospectively investigated. Out of them, 197 were tested positive and 188 negative for SARS-CoV-2. One hundred thirteen patients (57.36%) in the PCR+ group and 113 (60.11%) in the PCR- group had a diagnosis of PE. Complaints, respiratory rate, and oxygen saturation level in the blood (SpO2) were recorded at the first admission. Monocyte and eosinophil levels remained low, whereas FDR and PDR were higher in the PCR+ group. No difference was detected in ferritin, D-dimer levels, comorbidities, SpO2, and death rates between the two groups. Cough, fever, joint pain, and higher respiratory rate were more common in the PCR+ group. A decrease in white blood cell, monocyte, and eosinophil levels, whereas an increase in FDR and PDR levels may predict COVID-19 in patients with PE. PE patients complaining of cough, fever, and fatigue should undergo PCR testing as common symptoms. COVID-19 does not seem to increase the risk of mortality in patients with PE.

Senescent-like Blood Lymphocytes and Disease Progression in Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: Aging is known to exacerbate neuroinflammation, and in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), an older age is associated with a worse prognosis. We have previously shown the activation of cell senescence pathways in the proteome of peripheral blood mononuclear cells and the increase of proinflammatory cytokines in blood from individuals living with ALS. In this single-center, retrospective study, we investigated the expression of senescent-like blood mononuclear cells in ALS. METHODS: We first applied multidimensional cytometry by time-of-flight (CyTOF) to study the senescent immunophenotype of blood mononuclear cells from 21 patients with ALS and 10 healthy controls (HCs). We then used targeted flow cytometry (FC) to investigate frequencies of senescent blood lymphocytes in 40 patients with ALS and 20 HCs. Longitudinal analysis included 2 additional time points in 17 patients with ALS. Frequencies of senescent-like lymphocytes were analyzed in relation to survival. RESULTS: Unsupervised clustering of CyTOF data showed higher frequencies of senescent CD4+CD27-CD57+ T cells in patients with ALS compared with those in HCs (p = 0.0017, false discovery (FDR)-adjusted p = 0.029). Moderate to strong negative correlations were identified between CD4 T central memory-cell frequencies and survival (R = -061, p = 0.01; FDR-adjusted p < 0.1) and between CD95 CD8 cells and ALS functional rating scale revised at baseline (R = -0.72, p = 0.001; FDR-adjusted p < 0.1).Targeted FC analysis showed higher memory T regulatory cells (p = 0.0052) and memory CD8+ T cell (M-Tc; p = 0.0006) in bulbar ALS (A-B) compared with those in limb ALS (A-L), while late memory B cells (LM-B) were also elevated in A-B and fast-progressing ALS (p = 0.0059). Higher M-Tc levels separated A-B from A-L (AUC: 0.887; p < 0.0001). A linear regression model with prespecified clinical independent variables and neurofilament light chain plasma concentration showed that higher frequencies of LM-B predicted a shorter survival (hazard ratio: 1.094, CI: 1.026-1.167; p = 0.006). DISCUSSION: Our data suggest that a systemic elevation of senescent and late memory T and B lymphocytes is a feature of faster progressing ALS and of ALS individuals with bulbar involvement. Lymphocyte senescence and their memory state may be central to the immune dysregulation known to drive disease progression in ALS and a target for biomarkers and therapeutics discovery.

The Expression of Active CD11b Monocytes in Blood and Disease Progression in Amyotrophic Lateral Sclerosis.

Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and neurofilament light-chain plasma concentration at the baseline predicted shorter survival in a multivariable and univariate analysis (CD11b NCM­HR: 1.05, CI: 1.01−1.11, p = 0.013. Log rank: above median: 43 months and below median: 21.22 months; p = 0.0022). Blood samples with the highest frequencies of active CD11b+ IM and NCM contained the lowest concentrations of soluble CD11b. Our preliminary data suggest that the levels of active CD11b+ monocytes and NCM in the blood predict different clinical outcomes in ALS.

Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain.

The routine clinical integration of individualized objective markers of disease activity in those diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis is a key requirement for therapeutic development. A large, multicentre, clinic-based, longitudinal cohort was used to systematically appraise the leading candidate biofluid biomarkers in the stratification and potential therapeutic assessment of those with amyotrophic lateral sclerosis. Incident patients diagnosed with amyotrophic lateral sclerosis (n = 258), other neurological diseases (n = 80) and healthy control participants (n = 101), were recruited and followed at intervals of 3-6 months for up to 30 months. Cerebrospinal fluid neurofilament light chain and chitotriosidase 1 and blood neurofilament light chain, creatine kinase, ferritin, complement C3 and C4 and C-reactive protein were measured. Blood neurofilament light chain, creatine kinase, serum ferritin, C3 and cerebrospinal fluid neurofilament light chain and chitotriosidase 1 were all significantly elevated in amyotrophic lateral sclerosis patients. First-visit plasma neurofilament light chain level was additionally strongly associated with survival (hazard ratio for one standard deviation increase in log10 plasma neurofilament light chain 2.99, 95% confidence interval 1.65-5.41, P = 0.016) and rate of disability progression, independent of other prognostic factors. A small increase in level was noted within the first 12 months after reported symptom onset (slope 0.031 log10 units per month, 95% confidence interval 0.012-0.049, P = 0.006). Modelling the inclusion of plasma neurofilament light chain as a therapeutic trial outcome measure demonstrated that a significant reduction in sample size and earlier detection of disease-slowing is possible, compared with using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. This study provides strong evidence that blood neurofilament light chain levels outperform conventional measures of disease activity at the group level. The application of blood neurofilament light chain has the potential to radically reduce the duration and cost of therapeutic trials. It might also offer a first step towards the goal of more personalized objective disease activity monitoring for those living with amyotrophic lateral sclerosis.

Humoral response to neurofilaments and dipeptide repeats in ALS progression.

OBJECTIVE: To appraise the utility as biomarkers of blood antibodies and immune complexes to neurofilaments and dipeptide repeat proteins, the products of translation of the most common genetic mutation in amyotrophic lateral sclerosis (ALS). METHODS: Antibodies and immune complexes against neurofilament light, medium, heavy chains as well as poly-(GP)-(GR) dipeptide repeats were measured in blood samples from the ALS Biomarkers (n = 107) and the phenotype-genotype biomarker (n = 129) studies and in 140 healthy controls. Target analyte levels were studied longitudinally in 37 ALS cases. Participants were stratified according to the rate of disease progression estimated before and after baseline and C9orf72 genetic status. Survival and longitudinal analyses were undertaken with reference to matched neurofilament protein expression. RESULTS: Compared to healthy controls, total neurofilament proteins and antibodies, neurofilament light immune complexes (p < 0.0001), and neurofilament heavy antibodies (p = 0.0061) were significantly elevated in ALS, patients with faster progressing disease (p < 0.0001) and in ALS cases with a C9orf72 mutation (p < 0.0003). Blood neurofilament light protein discriminated better ALS from healthy controls (AUC: 0.92; p < 0.0001) and faster from slower progressing ALS (AUC: 0.86; p < 0.0001) compared to heavy-chain antibodies and light-chain immune complexes (AUC: 0.79; p < 0.0001 and AUC: 0.74; p < 0.0001). Lower neurofilament heavy antibodies were associated with longer survival (Log-rank Chi-square: 7.39; p = 0.0065). Increasing levels of antibodies and immune complexes between time points were observed in faster progressing ALS. CONCLUSIONS: We report a distinctive humoral response characterized by raising antibodies against neurofilaments and dipeptide repeats in faster progressing and C9orf72 genetic mutation carriers ALS patients. We confirm the significance of plasma neurofilament proteins in the clinical stratification of ALS.

Clinical, Neurophysiological and Neuroimaging Findings of Critical Illness Myopathy After COVID-19.

Hypoxemic respiratory failure caused by coronavirus disease 2019 (COVID-19) may lead to prolonged intensive care unit stay and mechanical ventilation. Critically ill patients often develop intensive care unit acquired weakness (ICUAW), which is an umbrella term that encompasses critical illness polyneuropathy and critical illness myopathy. The aim of this paper is to report the clinical, neurophysiological, and radiological findings suggesting critical illness myopathy in three patients with critical COVID-19. Muscle magnetic resonance imaging may serve as a diagnostic tool for critical illness myopathy. Weaning failure and generalized muscle weakness with preserved sensation and cranial nerve function should alert physicians for ICUAW.

Prevalence of Dementia and Mild Cognitive Impairment in a Rural Area of Sivas, Turkey.

Introduction The exact prevalence of dementia in Turkey is unknown. The purpose of this study was to determine the frequency of dementia in members of the population aged 60 years and older, as well as the influence of detailed sociodemographic factors on the prevalence rate in Sivas City Center, a large city in the middle of Anatolia, Turkey. Methods This was a cross-sectional, simple random sampling, door-to-door, population-based study. A total of 500 individuals aged 60 and older from the city center region of Sivas, Turkey, were involved. A sociodemographic data form, the Standardized Mini-Mental Test, the clock drawing test, the Cornell Scale for Depression in Dementia, and the Daily Life Activities and Instrumental Daily Life Activities tests were used in the screening phase. Results A total of 500 individuals ranging in age from 60 to 95 years were assessed. A total of 84 participants were diagnosed with dementia. The dementia prevalence was found to be 16.8% in Sivas city province. Dementia was associated with age (p<0.001), female sex (p<0.001), marital status (p<0.001), family income (p<0.001), and the absence of formal education (p<0.001). Conclusions This study is the first community-based study of cognitive impairment in Turkey, with a study design, procedures, and diagnostic criteria designed to determining the rate of dementia. Old age, a higher score on the Cornell Scale for Depression in Dementia, and a low educational level were independent risk factors for dementia. Further studies are required to confirm these results.

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients.

OBJECTIVE: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients. METHODS: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3-4 days during week 1. Based on lymphocyte count at week 4, patients received another 0-3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. RESULTS: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17-72) years and EDSS 0-8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data (n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data (n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. CONCLUSIONS: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

Socioeconomic status and disease-modifying therapy prescribing patterns in people with multiple sclerosis.

AIMS: To examine the association between socioeconomic status (SES) and disease-modifying therapy (DMT) prescribing patterns in people with relapsing-remitting multiple sclerosis (pwRRMS). METHODS: A cross-sectional analysis was conducted among pwRRMS treated with a DMT in the neuroinflammation service at The Royal London Hospital (Barts Health NHS Trust). Study data were collected between July and September 2017. SES was determined by patient income and education extracted from the English Index of Multiple Deprivation. Based on their efficacy, DMTs were categorized as moderate efficacy (Glatiramer Acetate and Beta-Interferons), high efficacy (Cladribine, Fingolimod and Dimethyl Fumarate) and very-high efficacy therapies (Natalizumab and Alemtuzumab). Multinomial logistic regressions were performed for univariate and multivariate models to assess differences between SES and DMT prescribing patterns. RESULTS: Treatment consisted of moderate efficacy (n = 76, 12%), high efficacy (n = 325, 51.3%) and very-high efficacy therapies (n = 232, 36.7%). Medians for income and education deciles were 4 (IQR 3-7) and 6 (IQR 4-8), respectively. After multinomial logistic regression analysis, patient income was not associated with increased odds of being treated with high efficacy (OR, 0.92; 95% CI, 0.82-1.04; p = 0.177) or very-high efficacy DMTs (OR, 0.95; 95% CI, 0.85-1.06; p = 0.371). Similarly, patient education was not associated with being treated with high efficacy (OR, 0.91; 95% CI, 0.80-1.03; p = 0.139) or very-high efficacy therapies (OR, 0.92; 95% CI, 0.81-1.04; p = 0.188). CONCLUSIONS: SES was not predictive of DMT prescribing patterns in pwRRMS. Whilst this appears reassuring within this universal health care setting, the same methodology needs to be applied to other MS services for comparison. Data could then be further interrogated to explore potential socioeconomic inequities in DMT prescribing patterns across the UK.

Serum NADPH oxidase concentrations and the associations with iron metabolism in relapsing remitting multiple sclerosis.

BACKGROUND: Overproduction of reactive oxygen species (ROS) and impaired iron metabolism are considered to be possible factors in the pathogenesis of Multiple sclerosis (MS). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the primary sources of regulated ROS production. The NADPH oxidase (NOX) family consists of seven catalytic homologues, NOX1-5 and two dual oxidases. NOX1 and NOX5 are associated with endothelial dysfunction and inflammation but NOX4 has a protective effect on vascular function. The aims of this study were to investigate the status of NOX1, NOX4 and NOX5 and its relationship with serum iron metabolism biomarkers in relapsing-remitting MS patients. METHODS: The study included 53 RRMS patients and 45 control subjects. Serum NOX1,4,5, ferritin, iron, unbound-iron binding capacity, C-reactive protein (CRP), white blood count (WBC) and erythrocyte sedimentation rate (ESR) levels were measured in all the study subjects. RESULTS: Higher serum NOX5 (p < 0.0001), CRP (p = 0.014), ferritin (p = 0.040) and lower serum NOX4 (p < 0.0001) and iron (p = 0.013) concentrations were found in the patients than in controls. No correlation was found between NOXs, CRP, WBC, ESR and iron metabolism biomarkers in patients. CONCLUSION: Our data suggest that increased NOX5 expression and decreased levels of NOX4 might be related with oxidative stress related vascular changes in MS patients. These findings provide future opportunities to combat MS with separately target individual NOX isoforms.

Prevalence of multiple sclerosis in an urban population of Sivas province in Turkey

Background/aim: Multiple sclerosis (MS) is a common neurological disorder that can be a leading cause of nontraumatic disability in several countries. Recent reports have indicated a moderate to high risk of MS in European countries. In this study, we examined the prevalence of MS in a well-defined urban population of provincial center in Sivas Province in Turkey. Materials and methods: This study sampled all registered residents of urban areas of provincial center in Sivas Province in April 2017 and 2018 January. All the included patients met the McDonald 2010 criteria. Medical records were reviewed, including all available previously acquired magnetic resonance imaging data. All patients were subsequently subjected to neurologic examination to confirm the MS diagnosis. Results: We identified 21 possible MS patients, with MS diagnosis confirmed in 19. The prevalence of MS was 288 per 100,000 inhabitants. Conclusion: For future studies, these high ratio results can be used in regional and national comparisons to determine cofactors contributing to the high prevalence of MS in our region and can help health-decision makers to better plan healthcare policies to improve neurological services and awareness about multifaceted clinical presentations of MS.

Treating the ineligible: Disease modification in people with multiple sclerosis beyond NHS England commissioning policies.

BACKGROUND: Whilst there is a broad selection of drugs licensed as disease modifying treatments (DMTs) for people with relapsing multiple sclerosis (pwRMS), access to DMTs remains restricted, particularly for people with progressive MS (pwPMS). Cladribine has shown efficacy at all stages of MS. Following withdrawal from the market of oral cladribine in 2011, partly due to issues associated with lymphopenia, and following a thorough risk assessment, we started using subcutaneously injected cladribine (Litak®) to treat both pwRMS and pwPMS. Here, we report on the real life safety and tolerability of this treatment option. METHODS: Cladribine was offered to (i) pwRMS as a choice despite fulfilling NHS England (NHSE) criteria for licensed DMTs, and (ii) pwRMS and pwPMS not eligible for NHSE approved DMTs. To avoid lymphocyte depletion lower than 0.5 × 109/l (WHO grade 2) cladribine was administered using a personalised dosing scheme (30-40 mg in week 1; and another 0-30 mg in week 5 pending total lymphocyte count at week 4). Anti-viral prophylaxis was given from day 1 for 60 days. Patients approaching week 48 were given a second treatment cycle. Data collection included side effects, relapses, change in disability and MRI indices. RESULTS: Seventy-one pwMS (40 female, 31 male; 36 RMS, 35 PMS,) received at least one treatment cycle. Mean age for starting cladribine was 44 years (range 22-72 years), median EDSS was 5 (range 1-8.5). Maximum follow-up was 28 months. 35/71 pwMS were followed up for at least 20 weeks. These patients had a median EDSS of 5.0 (range 1.0-7.5) at baseline and 5.5 (range 1.0-8.0) after a mean follow-up of 11 months (range 5-28). Cladribine was well tolerated with very few treatment-related adverse events observed. Personalised dosing led to grade 1-2 lymphopenia in 50% of cases. A single patient developed transient grade 3 lymphopenia. No cases of varicella or other infections were observed. Four/17 people with relapsing MS, experienced a total of six relapses during a mean follow-up of 13 months (range 5-28 months). In people with PMS (n = 18) median EDSS was 5.5 (2.0-7.5) at baseline and 6.0 (2.5-7.5) after a median of 10 months (range 5-18). In pwPMS MRI showed that 25% had active scans at baseline, and 0% at follow-up. CONCLUSION: Personalised dosing of cladribine avoided severe lymphopenia in all but one patients and was very well tolerated across a large spectrum of disease severity. Our data suggests cladribine may offer benefit people with relapsing and progressive MS alike. The personalised protocol used appears safe, however warrants controlled studies to more definitively assess efficacy and safety, particularly in groups of pwMS who are not eligible for licensed DMT including oral cladribine (Mavenclad®).

Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis.

BACKGROUND: It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology. Peripheral blood mononuclear cells alterations reflect the rate of progression of the disease representing an ideal biological substrate for biomarkers discovery. METHODS: We have applied TMTcalibrator™, a novel tissue-enhanced bio fluid mass spectrometry technique, to study the plasma proteome in ALS, using peripheral blood mononuclear cells as tissue calibrator. We have tested slow and fast progressing SOD1G93A mouse models of ALS at a pre-symptomatic and symptomatic stage in parallel with fast and slow progressing ALS patients at an early and late stage of the disease. Immunoassays were used to retest the expression of relevant protein candidates. RESULTS: The biological features differentiating fast from slow progressing mouse model plasma proteomes were different from those identified in human pathology, with only processes encompassing membrane trafficking with translocation of GLUT4, innate immunity, acute phase response and cytoskeleton organization showing enrichment in both species. Biological processes associated with senescence, RNA processing, cell stress and metabolism, major histocompatibility complex-II linked immune-reactivity and apoptosis (early stage) were enriched specifically in fast progressing ALS patients. Immunodetection confirmed regulation of the immunosenescence markers Galectin-3, Integrin beta 3 and Transforming growth factor beta-1 in plasma from pre-symptomatic and symptomatic transgenic animals while Apolipoprotein E differential plasma expression provided a good separation between fast and slow progressing ALS patients. CONCLUSIONS: These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention. The variance observed in the plasma proteomes may depend on different biological patterns of disease progression in human and animal model.

Cladribine: Off-label disease modification for people with multiple sclerosis in resource-poor settings?

BACKGROUND: A considerable number of people with multiple sclerosis (pwMS) live in low- and middle-income countries (LMIC), where lack of resource adversely affects access to effective disease-modifying treatment. OBJECTIVE: The objective of this commentary is to propose a useful cost-effective disease-modifying treatment option for pwMS in LMIC with potential high efficacy and high convenience to the pwMS and treating physician.Viewpoint: We propose using generic 2-chloro-2'-deoxyadenosine (cladribine), a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II and III trials to be a highly effective disease-modifying treatment for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high-income economies where an oral preparation has recently been licensed by the European Medicines Agency. CONCLUSION: Our viewpoint takes into account experience we have gathered over the past three years in the use of generic cladribine to treat pwMS. Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.

Varicella zoster virus infections in neurological patients: a clinical study.

BACKGROUND: Varicella zoster virus (VZV) reactivation is a common infectious disease in neurology and VZV the second most frequent virus detected in encephalitis. This study investigated characteristics of clinical and laboratory features in patients with VZV infection. METHODS: Two hundred eighty two patients with VZV reactivation that were hospitalized in the department of neurology in the time from 2005 to 2013 were retrospectively evaluated. Results from cerebrospinal fluid (CSF) analysis were available from 85 patients. RESULTS: Trigeminal rash was the most common clinical manifestation, followed by segmental rash, CNS infection, facial nerve palsy, postherpetic neuralgia, and radiculitis. MRI of the brain performed in 25/33 patients with encephalitis/meningitis did not show any signs of infection in the brain parenchyma. Only one patient showed contrast enhancement in the hypoglossal nerve. General signs of infection such as fever or elevated CRP values were found in only half of the patients. Furthermore, rash was absent in a quarter of patients with CNS infection and facial nerve palsy, and thus, infection could only be proven by CSF analysis. Although slight inflammatory CSF changes occurred in few patients with isolated rash, the frequency was clearly higher in patients with CNS infection and facial nerve palsy. CONCLUSION: Monosegmental herpes zoster is often uncomplicated and a diagnostic lumbar puncture is not essential. In contrast, CSF analysis is an essential diagnostic tool in patients with skin lesions and cranial nerve or CNS affection. In patients with neuro-psychiatric symptoms and inflammatory CSF changes analysis for VZV should be performed even in the absence of skin lesions.

Monocyte/high-density lipoprotein ratio predicts the mortality in ischemic stroke patients.

OBJECTIVE: The inflammatory process is a very important stage in the development and prognosis of acute ischemic stroke (AIS). The monocyte to high-density lipoprotein (HDL) ratio (MHR) is accepted as a novel marker for demonstrating inflammation. However, the role of MHR as a predictor of mortality in patients with AIS remains unclear. METHODS: We retrospectively enrolled 466 patients who were referred to our clinic within the first 24hours of symptom presentation and who were diagnosed with AIS between January 2008 and June 2016. Four hundred and eight controls of similar age and gender were also included. The patient group was classified into two groups according to 30-day mortality. The groups were compared in terms of monocyte counts, HDL, and MHR values. RESULTS: The patient group had significantly higher monocyte counts and lower HDL levels; therefore, this group had higher values of MHR compared to controls. Additionally, the monocyte count and MHR value were higher, and the HDL level was lower in non-surviving patients (p<0.001). The MHR value was also observed as a significant independent variable of 30-day mortality in patients with AIS (p<0.001). The optimum cut-off value of MHR in predicting the 30-day mortality for patients with AIS was 17.52 (95% CI 0.95-0.98). CONCLUSION: Our study demonstrated that a high MHR value is an independent predictor of 30-day mortality in patients with AIS.

The Effect of Eosinopenia on Mortality in Patients with Intracerebral Hemorrhage.

INTRODUCTION: Inflammation may determine the prognosis of intracerebral hemorrhage (ICH), which has high mortality and morbidity rates. Recent studies have increasingly demonstrated eosinopenia as a prognostic factor, particularly in bacteremia, chronic obstructive pulmonary disease, and myocardial and cerebral infarction. Nonetheless, its significance regarding the determination of prognosis in patients with ICH has not yet been clarified. MATERIALS AND METHODS: Our study included 296 patients who presented to our clinic within 24 hours of the onset of symptoms and who were diagnosed with ICH between January 2008 and June 2016, along with 180 age- and sex-matched controls. During their hospitalization, 120 of these 296 patients died. Patients and controls were compared in terms of neutrophil count/percentage and eosinophil count/percentage; these were also compared between nonsurviving and surviving patients. The significance of eosinopenia in predicting mortality was also evaluated. RESULTS: Patients had a significantly higher neutrophil count/percentage and a significantly lower eosinophil count/percentage than controls; these results were similar between nonsurviving and surviving patients (P < .001). Consequently, the patient group was divided into 4 subgroups depending on the presence of eosinopenia and/or neutrophilia. The mortality rate was highest (62%) in the group that had both eosinopenia and neutrophilia. Univariate and multivariate logistic regression analyses indicated that neutrophilia and eosinopenia were independent predictors of mortality in ICH (P = .002; P = .004) DISCUSSION: These results indicate that eosinopenia can occur in patients with ICH and that although the mechanism is unclear, eosinopenia is closely associated with mortality in these patients, particularly when accompanied by neutrophilia.